Activation of HTLV-I long terminal repeat by stress-inducing agents and protection of HTLV-I-Infected T-cells from apoptosis by the viral Tax protein

HTLV-I is etiologically implicated with tropical spastic paraparesis/HTLV-I associated myelopathy, adult T-cell leukemia and certain other diseases. H owever, after infection the virus enters into a dormant state, whereas the characteristics of the HTLV-I related diseases indicate that their genesis requires activation of the dormant virus by a Tax-independent mechanism. In the present study we demonstrate that a variety of stress-inducing agents (TPA, cisplatin, etoposide, taxol, and 3-methylcholanthrene) are capable of Tax-independent activation of HTLV-I LTR and that this activation is detec ted mainly in cells that are undergoing through the apoptotic process. Furt hermore, it is demonstrated that both apoptosis induction and HTLV-I LTR ac tivation are inhibited by Bcl-2 and by PKC, indicating that these two proce sses are mechanistically cross-linked. In addition, using an HTLV-I produci ng human T-cell line which permanently express the negatively transdominant tax mutant, Delta 58tax, under the Tet-Off control system, we prove that t he virally encoded Tax protein protects the host cells from apoptosis. Toge ther, these data suggest that activation of the dormant virus in the carrie rs' infected T-cells by certain stress-inducing conditions and protecting t hese cells from the consequent apoptotic death by the viral Tax protein eme rging after this activation, might be the basis for switching the virus fro m latency to a pathogenic phase. (C) 2001 Academic Press.